| abstract |
The discovery of mutant or fusion kinases that drive carcinogenesis, and the subsequent acquisition of specific inhibitors of these enzymes, has played a role in the treatment of certain cancers. However, the development of resistance remains a major clinical problem that limits the long-term efficacy of most such drugs. Here we demonstrate a strategy to overcome this resistance through drug-induced MEK cleavage (via direct precursor caspase-3 activation) combined with targeted kinase inhibition. This combined effect is prevalent across multiple tumor histologies (melanoma, lung cancer and leukemia) and driver mutations (mutated BRAF or EGFR, fusion kinases EML4‑ALK and BCR‑ABL). Caspase-3-mediated MEK kinase degradation results in sustained pathway inhibition and significantly delays or eliminates resistance in cancer cells in a manner superior to combination with MEK inhibitors. These data demonstrate the general significance of drug-mediated MEK kinase cleavage as a therapeutic strategy to prevent resistance to targeted anticancer therapies. |